BACKGROUND & AIMS Several studies have reported hepatitis C virus (HCV) RNA sequences in the circulation after treatment-induced or spontaneous recovery. We investigated whether the HCV RNA represents persistence of HCV infection or reinfection. METHODS We studied 117 patients who recovered from HCV infection (98 following therapy and 19 spontaneously). A reverse-transcription polymerase chain reaction assay was used to detect the 5'-untranslated region of HCV. T-cell responses were studied by enzyme-linked immunospot for interferon-γ. RESULTS Plasma samples from 15% of treatment-recovered patients and no spontaneously recovered patient tested positive for HCV RNA. Lymphocytes from 3 patients who responded to therapy and 1 who recovered spontaneously tested positive. The frequency of HCV RNA detection in plasma correlated inversely with the time after the end of treatment. Post-treatment HCV 5'-untranslated region sequences matched pretreatment sequences in 85% of cases. T-cell responses were significantly greater at time points with detectable trace amounts of HCV RNA than at time points without detectable HCV RNA (P = .035) and were primarily against nonstructural HCV antigens. The immune hierarchy was preserved over 5 years in patients whose post-treatment HCV RNA sequences matched pretreatment sequences, indicating HCV RNA persistence. An altered immune hierarchy with dominant immune responses, shifting from nonstructural to structural antigens, was observed in a single patient whose post-treatment HCV genotype differed from that of the pretreatment genotype, indicating HCV reinfection. CONCLUSIONS Trace amounts of HCV RNA of pretreatment sequence persisted and reappeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection. Reappearance of HCV RNA induced HCV-specific T-cell responses.